Manufacturing of small film strips

ABSTRACT

The present invention relates to methods for forming films. In particular, the present invention relates to the formation of films on a substrate via the use of individual pumps to deposit individual wet film products onto a substrate.

FIELD OF THE INVENTION

The present invention relates to methods for forming films. Inparticular, the present invention relates to the formation of films, inparticular, small film strips, on a substrate via the use of individualpumps.

BACKGROUND OF THE INVENTION

The use of films for the administration of active agents, such aspharmaceuticals, cosmetic and other materials, is becoming increasinglypopular. Such films should have a fairly uniform size, and asubstantially uniform distribution of components. The substantiallyuniform distribution of components is quite important when the filmsinclude pharmaceutical components, to ensure accurate dosages.

Films may be formed in any desired fashion, and in some cases it may beuseful to form a film on the surface of a substrate. The use of asubstrate to form film not only provides ease in processing but may alsoaid in packaging the film products. Typically, a wet film-forming matrixis deposited onto the surface of a substrate, and then dried to form theresulting film, which is then sized and cut into individual film stripproducts. Unfortunately, however, such typical processes result in agreat deal of wasted film due to the sizing and cutting process.

Further, traditional processing methods use one pumping mechanism withmultiple slot dies or other orifices. Such methods have a tendency todispense a wet film forming matrix unevenly through orifices, givingirregular and non-uniform dosages. In addition, in the case of filmmatrices having a high solid or particle content, the orifices may havea tendency to become blocked. The use of one pumping mechanism formultiple orifices may not provide enough pressure to release the blockedorifice, resulting in certain orifices dispensing higher amounts of thefilm-forming matrix. Thus, the end result of such traditional processingis a potential for uneven dosaging and products that lack compositionaluniformity.

The present invention seeks to solve the problems incurred withtraditional film processing, such as by providing a method thatcontinuously produces film products without the need for sizing the filmproducts, while at the same time providing uniform film dosages.

SUMMARY OF THE INVENTION

In one embodiment of the present invention, there is provided a methodof forming a plurality of individual film products, including the stepsof: (a) providing a reservoir housing a film forming matrix; (b)providing a plurality of individual volumetric pumps in association withthe reservoir; (c) providing a plurality of orifices, where each orificeis associated with an individual volumetric pump; (d) feeding the filmforming matrix from the reservoir to the individual volumetric pumps;(e) dispensing a predetermined amount of the film forming matrix fromeach of the volumetric pumps through an orifice associated therewith;and (f) extruding an individual wet film product onto a substrate.

Other embodiments of the present invention may provide a method offorming a plurality of individual film strips, including the steps of:(a) providing a reservoir housing a film forming matrix; (b) providing aplurality of individual metering pumps in association with thereservoir; (c) providing a plurality of orifices, where each orifice isassociated with an individual metering pump; (d) feeding the filmforming matrix from the reservoir to the plurality of individualmetering pumps; (e) dispensing a predetermined amount of the filmforming matrix from each of the metering pumps through an orificeassociated therewith; and (f) extruding an individual wet film stripthrough the orifice onto a substrate.

In another embodiment of the present invention, there is provided anapparatus for forming a plurality of individual film products,including: a reservoir for housing a film forming matrix; a plurality ofindividual volumetric pumps associated with the reservoir; a pluralityof orifices, each orifice being associated with a volumetric pump; asubstrate; and a means for moving the substrate through the apparatus.

In yet another embodiment of the present invention, there is provided amethod of forming a plurality of individual film patches, including thesteps of: (a) providing a substrate including a first polymericmaterial, the substrate having a top surface, where the substratecontinuously moves in a first direction; (b) providing a reservoirhousing a film forming matrix, the film forming matrix including asecond polymeric material and an active; (c) providing a plurality ofindividual volumetric pumps in association with the reservoir; (d)providing a plurality of orifices, where each orifice is associated withan individual volumetric pump, where each orifice is separated from eachother by a gap; (e) feeding the film forming matrix from the reservoirto the individual volumetric pumps; (f) dispensing a predeterminedamount of the film forming matrix from each of the volumetric pumpsthrough an orifice associated therewith; (g) extruding the predeterminedamount of the film forming matrix onto the top surface of the substrateas the substrate moves in the first direction to form a plurality ofindividual wet film products; and (h) drying the individual wet filmproducts to form a plurality of patches including a first layer ofsubstrate and a second layer of dried film products.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a depiction of one embodiment of the present invention that iscapable of forming individual film products.

FIG. 2 is a depiction of a second embodiment of the present inventionthat is capable of forming individual film strips.

FIGS. 3A and 3B are depictions of film patches formed by an alternateembodiment of the present invention.

FIG. 4 is a depiction of a further embodiment of the present inventionthat is capable of forming a substrate and a plurality of individualfilm products on the surface of the substrate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to methods and apparatuses designed forforming film products, including film products that include at least oneactive composition. Specifically, the invention relates to methods offorming film products on a substrate, while maintaining the uniformityof content and the structural integrity of the individual film product.Further, the invention provides a method and apparatus for forming filmproducts that minimizes the amount of waste typically required in filmprocessing. Film systems embody a field of technology that has majoradvantages in areas of administering drug, medicament, and various otheractive and agent delivery systems to an individual in need thereof. Inorder to provide a desirable final product that exhibits advantageouscharacteristics and desirable properties, including uniformity ofcontent, the processing and manufacturing of film strips and filmtechnology is technologically demanding and cumbersome.

As used herein, the terms “pharmaceutical”, “medicament”, “drug” and“active” may be used interchangeably, and refer to a substance orcomposition useful for the prevention or treatment of a condition. Theterms may include pharmaceuticals, neutraceuticals, cosmetic agents,biologic agents, bioeffective substances, and the like.

It will be understood that the term “film” includes delivery systems ofany thickness, including films and film strips, sheets, discs, wafers,and the like, in any shape, including rectangular, square, or otherdesired shape. The film may be in the form of a continuous roll of filmor may be sized to a desired length and width. The films describedherein may be any desired thickness and size suitable for the intendeduse. For example, a film of the present invention may be sized such thatit may be placed into the oral cavity of the user. Other films may besized for application to the skin of the user, i.e., a topical use. Forexample, some films may have a relatively thin thickness of from about0.1 to about 10 mils, while others may have a somewhat thicker thicknessof from about 10 to about 30 mils. For some films, especially thoseintended for topical use, the thickness may be even larger, i.e.,greater than about 30 mils. In addition, the term “film” includessingle-layer compositions as well as multi-layer compositions, such aslaminated films, coatings on films and the like. The composition in itsdried film form maintains a uniform distribution of components throughthe processing of the film. Films may include a pouch or region ofmedicament between two films.

The term “patch” as used herein is intended to include multi-layeredfilm products, where the first layer (or “backing layer”) is a filmproduct that has a slower rate of dissolution than the second layer (or“active layer”). Patches described herein generally include the firstand second layers adhered or laminated to each other, where the secondlayer has a smaller length and/or width of the first layer, such that atleast a portion of the surface of the first layer is visible outside ofthe second layer (including, but not limited to, the design shown inFIG. 3B and described in further detail herein).

Films formed by the present invention may be suitable for administrationto at least one region of the body of the user, such as mucosal regionsor regions within the body of the user, such as on the surface ofinternal organs. In some embodiments of the invention, the films areintended for oral administration. In other embodiments, the films areintended for topical administration. As used herein, the term “topicalagent” is meant to encompass active agents that are applied to aparticular surface area. For example, in one embodiment, a topical agentis applied to an area of the skin. In other embodiments, the topicalagent may also be applied to mucosal areas of the body, such as the oral(e.g., buccal, sublingual, tongue), vaginal, ocular and anal areas ofthe body. In still other embodiments, the topical agent is applied to aninternal organ or other body surface of the user, such as duringsurgery, where the agent may be removed or left within the body aftersurgery is complete. In other embodiments, a topical agent is applied toa hard surface, such as a particular surface area in need of treatment.In other embodiments, the films of the present invention are ingestible,and are intended to be placed in the mouth of the user and swallowed asthe film disintegrates.

The medicament may be dispersed throughout the film, or it may bedeposited onto one or more surfaces of the film. In either way, it isdesirable that the amount of medicament per unit area is substantiallyuniform throughout the film. The “unit area” is intended to include asuitable unit area, such as the area of one typical dosage unit. It isdesired that the films of the present invention include a uniformity ofcomponent distribution throughout the volume of a given film. Suchuniformity includes a substantially uniform amount of medicament perunit volume of the film, whether the medicament is within the matrix ofthe film or coated, laminated, or stabilized on one or more surfacesthereof. When such films are cut into individual units, the amount ofthe agent in the unit can be known with a great deal of accuracy. Forthe films formed herein, it is understood by one of ordinary skill inthe art that the resulting film is not required to be exactly 100%uniform. All that is required is that the film be “substantiallyuniform”, i.e., a slight amount of non-uniformity is understood to beacceptable. “Substantially uniform” may include, for example, a filmthat is about 90% uniform in content from one region of the film toanother, or a film that is about 95% uniform in content from one regionof the film to another, and most desirably about 99% uniform in contentfrom one region of the film to another.

It is desirable that any individual film products formed by the presentinvention (i.e., products having a substantially similar mass andvolume) be substantially uniform in content with respect to each other.That is, the individual film products (including individual dosages ofapproximately equal sizes) formed by the present invention should haveapproximately the same content composition as each other film product.Of course, it will be understood that some deviation is to be expectedduring the manufacturing process, but desirably the individual filmproducts should be at least 90% uniform in content with respect to eachother. In other words, “substantially uniform” may mean that individualfilm products should vary by no more than about 10% with respect to eachother. In some embodiments, “substantially uniform” may mean thatindividual film products should vary by no more than about 5% withrespect to each other.

Uniformity of medicament throughout the film is important inadministering an accurate and effective dose of medicament to a user.Various methods of forming uniform films, as well as various polymers,additives and fillers, may be used, including those methods andmaterials described in U.S. Pat. Nos. 7,425,292, 7,357,891 and7,666,337, which are herein incorporated by reference in theirentireties. Any number of active components or pharmaceutical agents maybe included in the films discussed herein. The active component(s) maybe disposed within any layer of film products formed herein or they maybe placed onto one or more surfaces of the film products.

Examples of useful drugs include ace-inhibitors, antianginal drugs,anti-arrhythmias, anti-asthmatics, anti-cholesterolemics, analgesics,anesthetics, anti-convulsants, anti-depressants, anti-diabetic agents,anti-diarrhea preparations, antidotes, anti-histamines,anti-hypertensive drugs, anti-inflammatory agents, anti-lipid agents,anti-manics, anti-nauseants, anti-stroke agents, anti-thyroidpreparations, anti-tumor drugs, anti-viral agents, acne drugs,alkaloids, amino acid preparations, anti-tussives, anti-uricemic drugs,anti-viral drugs, anabolic preparations, systemic and non-systemicanti-infective agents, anti-neoplastics, anti-parkinsonian agents,anti-rheumatic agents, appetite stimulants, biological responsemodifiers, blood modifiers, bone metabolism regulators, cardiovascularagents, central nervous system stimulates, cholinesterase inhibitors,contraceptives, decongestants, dietary supplements, dopamine receptoragonists, endometriosis management agents, enzymes, erectile dysfunctiontherapies, fertility agents, gastrointestinal agents, homeopathicremedies, hormones, hypercalcemia and hypocalcemia management agents,immunomodulators, immunosuppressives, migraine preparations, motionsickness treatments, muscle relaxants, obesity management agents,osteoporosis preparations, oxytocics, parasympatholytics,parasympathomimetics, prostaglandins, psychotherapeutic agents,respiratory agents, sedatives, smoking cessation aids, sympatholytics,tremor preparations, urinary tract agents, vasodilators, laxatives,antacids, ion exchange resins, anti-pyretics, appetite suppressants,expectorants, anti-anxiety agents, anti-ulcer agents, anti-inflammatorysubstances, coronary dilators, cerebral dilators, peripheralvasodilators, psycho-tropics, stimulants, anti-hypertensive drugs,vasoconstrictors, migraine treatments, antibiotics, tranquilizers,anti-psychotics, anti-tumor drugs, anti-coagulants, anti-thromboticdrugs, hypnotics, anti-emetics, anti-nauseants, anti-convulsants,neuromuscular drugs, hyper- and hypo-glycemic agents, thyroid andanti-thyroid preparations, diuretics, anti-spasmodics, terine relaxants,anti-obesity drugs, erythropoietic drugs, anti-asthmatics, coughsuppressants, mucolytics, DNA and genetic modifying drugs, andcombinations thereof.

Examples of medicating active ingredients contemplated for use in thepresent invention include antacids, H₂-antagonists, and analgesics. Forexample, antacid dosages can be prepared using the ingredients calciumcarbonate alone or in combination with magnesium hydroxide, and/oraluminum hydroxide. Moreover, antacids can be used in combination withH₂-antagonists.

Analgesics include opiates and opiate derivatives, such as oxycodone(commercially available as Oxycontin®); ibuprofen (commerciallyavailable as Motrin®, Advil®, Motrin Children's®, Motrin IB®), AdvilChildren's®, Motrin Infants'®, Motrin Junior®, Ibu-2®, Proprinal®,Ibu-200®, Midol Cramp Formula®, Bufen®, Motrin Migraine Pain®, Addaprin®and Haltran®), aspirin (commercially available as Empirin®, Ecotrin®,Genuine Bayer®, and Halfprin®), acetaminophen (commercially available asSilapap Infant's®, Silapap Children's®, Tylenol®, Tylenol Children's®,Tylenol Extra Strength®, Tylenol Infants' Original®, Tylenol Infants'®,Tylenol Arthritis®, T-Painol®, Q-Pap®, Cetafen®, Dolono®, Tycolene®,APAP® and Aminofen®), and combinations thereof that may optionallyinclude caffeine. Other pain relieving agents may be used in the presentinvention, including meperidine hydrochloride (commercially available asDemerol®), capsaicin (commercially available as Qutenza®), morphinesulfate and naltrexone hydrochloride (commercially available asEmbeda®), hydromorphone hydrochloride (commercially available asDilaudid®), propoxyphene napsylate and acetaminophen (commerciallyavailable as Darvocet-N®), Fentanyl (commercially available asDuragesic®, Onsolis®, and Fentora®), sodium hyaluronate (commerciallyavialble as Euflexxa®), adalimumab (commercially available as Humira®),sumatriptan succinate (commercially available as Imitrex®), fentanyliontophoretic (commercially available as Ionsys®), orphenadrine citrate(commercially available as Norgesic®), magnesium salicylate tetrahydrate(commercially available as Novasal®), oxymorphone hydrochloride(commercially available as Opana ER®), methocarbamol (commerciallyavailable as Robaxin®), carisoprodol (commercially available as Soma®),tramadol hydrochloride (commercially available as Ultracet® andUltram®), morphine sulfate (commercially available as MS Contin®),metaxalone (commercially available as Skelaxin®), oxycodonehydrochloride (commercially available as OxyContin®),acetaminophen/oxycodone hydrochloride (commercially available asPercocet®), oxycodone/aspirin (commercially available as Percodan®),hydrocodone bitartrate/acetaminophen (commercially available asVicodin®), hydrocodone bitartrate/ibuprofen (commercially available asVicoprofen®), nepafenac (commercially available as Nevanac®), andpregabalin (commercially available as Lyrica®).

The present invention may further include agents such as NSAIDs,including etodolac (commercially available as Lodine®), ketorolactromethamine (commercially available as Acular® or Acuvail®), naproxensodium (commercially available as Anaprox®, Naprosyn®), flurbiprofen(commercially available as Ansaid®), diclofenac sodium/misoprostol(commercially available as Arthrotec®), celecoxib (commerciallyavailable as Celebrex®), sulindac (commercially available as Clinoril®),oxaprozin (commercially available as Daypro®), piroxicam (commerciallyavailable as Feldene®), indomethacin (commercially available asIndocin®), meloxicam (commercially available as Mobic®), mefenamic acid(commercially available as Ponstel®), tolmetin sodium (commerciallyavailable as Tolectin®), choline magnesium trisalicylate (commerciallyavailable as Trilisate®), diclofenac sodium (commercially available asVoltaren®), diclofenac potassium (commercially available as Cambia® orZipsor®), and misoprostol (commercially available as Cytotec®). Opiateagonists and antagonists, such as buprenorphine and naloxone are furtherexamples of drugs for use in the present invention.

Other preferred drugs for other preferred active ingredients for use inthe present invention include anti-diarrheals such as loperamide(commercially available as Imodium ADC), Imotil®, Kaodene®, Imperim®,Diamode®, QC Anti-Diarrheal®, Health Care America Anti-Diarrheal®,Leader A-D®, and Imogen®), nitazoxanide (commercially available asAlinia®) and diphenoxylate hydrochloride/atropine sulfate (commerciallyavailable as Lomotil®), anti-histamines, anti-tussives, decongestants,vitamins, and breath fresheners. Common drugs used alone or incombination for colds, pain, fever, cough, congestion, runny nose andallergies, such as acetaminophen, ibuprofen, chlorpheniramine maleate,dextromethorphan, dextromethorphan HBr, phenylephrine HCl,pseudoephedrine HCl, diphenhydramine and combinations thereof, such asdextromethophan HBr and phenylephrine HCl (available as Triaminic®) maybe included in the film compositions of the present invention.

Other active agents useful in the present invention include, but are notlimited to alcohol dependence treatment, such as acamprosate calcium(commercially available as Campral®); Allergy treatment medications,such as promethazine hydrochloride (commercially available asPhenergan®), bepotastine besilate (commercially available as Bepreve®),hydrocodone polistirex/chlorpheniramine polistirex (commerciallyavailable as Tussionex®), cetirizine hydrochloride (commerciallyavailable as Zyrtec®), cetirizine hydrochloride/pseudoephedrinehydrochloride (commercially available as Zyrtec-D®), promethazinehydrochloride/codeine phosphate (commercially available as Phenergan®with Codeine), pemirolast (commercially available as Alamast®),fexofenadine hydrochloride (commercially available as Allegra®),meclizine hydrochloride (commercially available as Antivert®),azelastine hydrochloride (commercially available as Astelin®),nizatidine (commercially available as Axid®), desloratadine(commercially available as Clarinex®), cromolyn sodium (commerciallyavailable as Crolom®), epinastine hydrochloride (commercially availableas Elestat®), azelastine hydrochloride (commercially available asOptivar®), prednisolone sodium phosphate (commercially available asOrapred ODT®), olopatadine hydrochloride (commercially available asPatanol®), ketotifen fumarate (commercially available as Zaditor®), andmontelukast sodium (commercially available as Singulair®); andanti-histamines such as diphenhydramine HCl (available as Benadryl®),loratadine (available as Claritin®), astemizole (available asHismanal®), nabumetone (available as Relafen®), diphenydramine HCL(available as TheraFlu®) and clemastine (available as Tavist®).

Films of the present invention may further include Alzheimer's treatmentmedications, such as tacrine hydrochloride (commercially available asCognex®), galantamine (commercially available as Razadyne®), donepezilhydrochloride (commercially available as Aricept®), rivastigminetartrate (commercially available as Exelon®), caprylidene (commerciallyavailable as Axona®), and memantine (commercially available asNamenda®); anemia medication, such as cyanocobalamin (commerciallyavailable as Nascobal®) and ferumoxytol (commercially available asFeraheme®); anesthetics, such as antipyrine with benzocaine(commercially available as Auralgan®, Aurodex® and Auroto®); anginamedication, such as amlodipine besylate (commercially available asNorvasc®), nitroglycerin (commercially available as Nitro-Bid®,Nitro-Dur®, Nitrolingual®, Nitrostat®, Transderm-Nitro®), isosorbidemononitrate (commercially available as Imdur®), and isosorbide dinitrate(commercially available as Isordil®); anti-tussives such as guaifensin;anti-Alzheimer's agents, such as nicergoline; and Ca^(H)-antagonistssuch as nifedipine (commercially available as Procardia® and Adalat®).

Actives useful in the present invention may also includeanti-asthmatics, such as albuterol sulfate (commercially available asProventil®), ipratropium bromide (commercially available as Atrovent®),salmeterol xinafoate (commercially available as Serevent®), zafirlukast(commercially available as Accolate®), flunisolide (commerciallyavailable as AeroBid®), metaproterenol sulfate (commercially availableas Alupent®), albuterol inhalation (commercially available asVentolin®), terbutaline sulfate (commercially available as Brethine®),formoterol (commercially available as Foradil®), cromolyn sodium(commercially available as Intal®), levalbuterol hydrochloride(commercially available as Xopenex®), zileuton (commercially availableas Zyflo®), fluticasone propionate/salmeterol (commercially available asAdvair®), albuterol sulfate/triamcinolone acetonide (commerciallyavailable as Azmacort®), dimethylxanthine (commercially available asTheophylline®), and beclomethasone (commercially available asBeclovent®, Beconase®, Qvar®, Vancenase®, Vanceril®); angioedemamedication, such as C1 esterase Inhibitor (human) (commerciallyavailable as Berinert®) and ecallantide (commercially available asKalbitor®); and antibacterial medications, such astrimethoprim/sulfamethoxazole (commercially available as Bactrim®),mupirocin (commercially available as Bactroban®), metronidazole(commercially available as Flagyl®), sulfisoxazole acetyl (commerciallyavailable as Gantrisin®), bismuth subsalicylate andmetronidazole/tetracycline hydrochloride (commercially available asHelidac Therapy®), nitrofurantoin (commercially available asMacrodantin®), norfloxacin (commercially available as Noroxin®),erythromycin ethylsuccinate/Sulfisoxazole acetyl (commercially availableas Pediazole®), and levofloxacin (commercially available as Levaquin®).

The present invention may further include one or more Antibiotics,including amoxicillin (commercially available as Amoxil®), ampicillin(commercially available as Omnipen®, Polycillin® and Principen®),amoxicillin/clavulanate potassium (commercially available asAugmentin®), moxifloxacin hydrochloride (commercially available asAvelox®), besifloxacin (commercially available as Besivance®),clarithromycin (commercially available as Biaxin®), ceftibuten(commercially available as Cedax®), cefuroxime axetil (commerciallyavailable as Ceftin®), cefprozil (commercially available as Cefzil®),ciprofloxacin hydrochloride (commercially available as Ciloxan® andCipro®), clindamycin phosphate (commercially available as Cleocin T®),doxycycline hyclate (commercially available as Doryx®), dirithromycin(commercially available as Dynabac®), erythromycin (commerciallyavailable as E.E.S.®, E-Mycin®, Eryc®, Ery-Tab®, Erythrocin®, and PCE®),erythromycin topical (commercially available as A/T/S®, Erycette®,T-Stat®), gemifloxacin (commercially available as Factive®), ofloxacin(commercially known as Ocuflox®, Floxin®), telithromycin (commerciallyavailable as Ketek®), lomefloxacin hydrochloride (commercially availableas Maxaquin®), minocycline hydrochloride (commercially available asMinocin®), fosfomycin tromethamine (commercially available as Monurol®),penicillin with potassium (commercially available as Penicillin VK®,Veetids®), trimethoprim (commercially available as Primsol®),ciprofloxacin hydrochloride (commercially available as Proquin XR®),rifampin, isoniazid and pyrazinamide (commercially available asRifater®), cefditoren (commercially available as Spectracef®), cefixime(commercially available as Suprax®), tetracycline (commerciallyavailable as Achromycin V® and Sumycin®), tobramycin (commerciallyavailable as Tobrex®), rifaximin (commercially available as Xifaxan®),azithromycin (commercially available as Zithromax®), azithromycinsuspension (commercially available as Zmax®), linezolid (commerciallyavailable as Zyvox®), benzoyl peroxide and clindamycin (commerciallyavailable as BenzaClin®), erythromycin and benzoyl peroxide(commercially available as Benzamycin®), dexamethasone (commerciallyavailable as Ozurdex®), ciprofloxacin and dexamethasone (commerciallyavailable as Ciprodex®), polymyxin B sulfate/neomycinsulfate/hydrocortisone (commercially available as Cortisporin®),colistin sulfate/neomycin sulfate/hydrocortisone acetate/thonzoniumbromide (commercially available as Cortisporin-TC Otic®), cephalexinhydrochloride (commercially available as Keflex®), cefdinir(commercially available as Omnicef®), and gatifloxacin (commerciallyavailable as Zymar®).

Other useful actives include cancer treatment medications, includingcyclophosphamide (commercially available as Cytoxan®), methotrexate(commercially available as Rheumatrex® and Trexal®), tamoxifen citrate(commercially available as Nolvadex®), bevacizumab (commerciallyavailable as Avastin®), everolimus (commercially available asAfinitor®), pazopanib (commercially available as Votrient®), andanastrozole (commercially available as Arimidex®); leukemia treatment,such as ofatumumab (commercially available as Arzerra®); anti-thromboticdrugs, such as antithrombin recombinant lyophilized powder (commerciallyavailable as Atryn®), prasugrel (commercially available as Efient®);anti-coagulants, such as aspirin with extended-release dipyridamole(commercially available as Aggrenox®), warfarin sodium (commerciallyavailable as Coumadin®), dipyridamole (commercially available asPersantine®), dalteparin (commercially available as Fragmin®),danaparoid (commercially available as Orgaran®), enoxaparin(commercially available as Lovenox®), heparin (commercially available asHep-Lock, Hep-Pak, Hep-Pak CVC, Heparin Lock Flush), tinzaparin(commercially available as Innohep®), and clopidogrel bisulfate(commercially available as Plavix®); antiemetics, such as granisetronhydrochloride (commercially available as Kytril®) and nabilone(commercially available as Cesamet®), trimethobenzamide hydrochloride(commercially available as Tigan®), and ondansetron hydrochloride(commercially available as Zofran®); anti-fungal treatment, such asketoconazole (commercially available as Nizoral®), posaconazole(commercially available as Noxafil®), ciclopirox (commercially availableas Penlac®), griseofulvin (commercially available as Gris-PEG®),oxiconazole nitrate (commercially available as Oxistat®), fluconazole(commercially available as Diflucan®), sertaconazole nitrate(commercially available as Ertaczo®), terbinafine hydrochloride(commercially available as Lamisil®), ciclopirox (commercially availableas Loprox®), nystatin/triamcinolone acetonide (commercially available asMycolog-II®), econazole nitrate (commercially available as Spectazole®),itraconazole (commercially available as Sporanox®), and terconazole(commercially available as Terazol®).

Active agents may further include anti-inflammatory medications, such ashydroxychloroquine sulfate (commercially available as Plaquenil®),fluticasone propionate (commercially available as Cutivate®),canakinumab (commercially available as Llaris®), amcinonide(commercially available as Cyclocort®), methylprednisolone (commerciallyavailable as Medrol®), budesonide (commercially available as EntocortEC®), anakinra (commercially available as Kineret®), diflorasonediacetate (commercially available as Psorcon®), and etanercept(commercially available as Enbrel®); antispasmodic medication, such asphenobarbital/hyoscyamine sulfate/atropine sulfate/scopolaminehydrobromide (commercially available as Donnatal®); antiviral treatment,such as oseltamivir phosphate (commercially available as Tamiflu®);anti-parasites medication, including tinidazole (commercially availableas Tindamax®); appetite treatment mediations, such as megestrol acetate(commercially available as Megace ES®), phentermine hydrochloride(commercially available as Adipex-P®), and diethylpropion hydrochloride(commercially available as Tenuate®); arthritis medications, includingleflunomide (commercially available as Arava®), certolizumab pegol(commercially available as Cimzia®), diclofenac sodium (commerciallyavailable as Pennsaid®), golimumab (commercially available as Simponi®),and tocilizumab (commercially available as Actemra®); bladder controlmedication, such as trospium chloride (commercially available asSanctura®), desmopressin acetate (commercially available as DDAVP®),tolterodine tartrate (commercially available as Detrol®), oxybutyninchloride (commercially available as Ditropan® or Gelnique®), darifenacin(commercially available as Enablex®), and solifenacin succinate(commercially available as VESIcare®); blood vessel constrictors, suchas methylergonovine maleate (commercially available as Methergine®);plasma uric managers, such as rasburicase (commercially available asElitek®); iron deficiency anemia medications, such as ferumoxytol(commercially available as Feraheme®); lymphoma medications, such aspralatrexate (commercially available as Folotyn®), romidepsin(commercially available as Isodax®); malaria medication, such asartemether/lumefantrine (commercially available as Coartem®);hyponatremia medication, such as tolvatpan (commercially available asSamsca®); medication for treatment of von Willebrand disease(commercially available as Wilate®); anti-hypertension medications, suchas treprostinil (commercially available as Tyvaso®), tadalafil(commercially available as Adcirca®); cholesterol lowering medication,including paricalcitol (commercially available as Altocor®),pitavastatin (commercially available as Livalo®), lovastatin, niacin(commercially available as Advicor®), colestipol hydrochloride(commercially available as Colestid®), rosuvastatin calcium(commercially available as Crestor®), fluvastatin sodium (commerciallyavailable as Lescol®), atorvastatin calcium (commercially available asLipitor®), lovastatin (commercially available as Mevacor®), niacin(commercially available as Niaspan®), pravastatin sodium (commerciallyavailable as Pravachol®), pavastatin sodium with buffered aspirin(commercially available as Pravigard PAC®), cholestyramine (commerciallyavailable as Questran®), simvastatin and niacin (commercially availableas Simcor®), atenolol, chlorthalidone (commercially available asTenoretic®), atenolol (commercially available as Tenormin®), fenofibrate(commercially available as Tricor®), fenofibrate (commercially availableas Triglide®), ezetimibe/simvastatin (commercially available asVytorin®), colesevelam (commercially available as WelChol®), bisoprololfumarate (commercially available as Zebeta®), ezetimibe (commerciallyavailable as Zetia®), bisoprolol fumarate/hydrochlorothiazide(commercially available as Ziac®), and simvastatin (commerciallyavailable as Zocor®).

The actives included herein may also include chronic kidney diseasemedication, such as paricalcitol (commercially available as Zemplar®);contraceptive agents, including etonogestrel (commercially available asImplanon®), norethindrone acetate, ethinyl estradiol (commerciallyavailable as Loestrin 24 FE®), ethinyl estradiol, norelgestromin(commercially available as Ortho Evra®), levonorgestrel (commerciallyavailable as Plan B®), levonorgestrel and ethinyl estradiol(commercially available as Preven®), levonorgestrel, ethinyl estradiol(commercially available as Seasonique®), and medroxyprogesterone acetate(commercially available as Depo-Provera®); COPD medication, such asarformoterol tartrate (commercially available as Brovana®) andipratropium bromide, albuterol sulfate (commercially available asCombivent®); cough suppressants, including benzonatate (commerciallyavailable as Tessalon®), guaifenesin, codeine phosphate (commerciallyavailable as Tussi-Organidin NR®), and acetaminophen, codeine phosphate(commercially available as Tylenol with Codeine®); medication for thetreatment of diabetes, including pioglitazone hydrochloride, metforminhydrochloride (commercially available as ACTOplus Met®), bromocriptinemesylate (commercially available as Cycloset®), liraglutide(commercially available as Victoza®), saxagliptin (commerciallyavailable as Onglyza®), pioglitazone hydrochloride (commerciallyavailable as Actos®), glimepiride (commercially available as Amaryl®),rosiglitazone maleate, metformin hydrochloride (commercially availableas Avandamet®), rosiglitazone maleate (commercially available asAvandaryl®), rosiglitazone maleate (commercially available as Avandia®),exenatide (commercially available as Byetta®), chlorpropamide(commercially available as Diabinese®), pioglitazone hydrochloride,glimepiride (commercially available as Duetact®), metforminhydrochloride (commercially available as Glucophage®), glipizide(commercially available as Glucotrol®), glyburide, metformin(commercially available as Glucovance®), metformin hydrochloride(commercially available as Glumetza®), sitagliptin (commerciallyavailable as Januvia®), detemir (commercially available as Levemir®),glipizide, metformin hydrochloride (commercially available asMetaglip®), glyburide (commercially available as Micronase®),repaglinide (commercially available as Prandin®), acarbose (commerciallyavailable as Precose®), nateglinide (commercially available asStarlix®), pramlintide acetate (commercially available as Symlin®), andtolazamide (commercially available as Tolinase®).

Other useful agents of the present invention may include digestiveagents, such as sulfasalazine (commercially available as Azulfidine®),rabeprazole sodium (commercially available as AcipHex®), lubiprostone(commercially available as Amitiza®), dicyclomine hydrochloride(commercially available as Bentyl®), sucralfate (commercially availableas Carafate®), lactulose (commercially available as Chronulac®),docusate (commercially available as Colace®), balsalazide disodium(commercially available as Colazal®), losartan potassium (commerciallyavailable as Cozaar®), olsalazine sodium (commercially available asDipentum®), chlordiazepoxide hydrochloride, clidinium bromide(commercially available as Librax®), esomeprazole magnesium(commercially available as Nexium®), famotidine (commercially availableas Pepcid®), lansoprazole (commercially available as Prevacid®),lansoprazole and naproxen (commercially available as PrevacidNapraPAC®), amoxicillin/clarithromycin/lansoprazole (commerciallyavailable as Prevpac®), omeprazole (commercially available asPrilosec®), pantoprazole sodium (commercially available as Protonix®),metoclopramide hydrochloride (commercially available as Reglan® orMetozolv®), cimetidine (commercially available as Tagamet®), ranitidinehydrochloride (commercially available as Zantac®), and omeprazole,sodium bicarbonate (commercially available as Zegerid®); diuretics,including spironolactone, hydrochlorothiazide (commercially available asAldactazide®), spironolactone (commercially available as Aldactone®).bumetanide (commercially available as Bumex®), torsemide (commerciallyavailable as Demadex®), chlorothiazide (commercially available asDiuril®), furosemide (commercially available as Lasix®), metolazone(commercially available as Zaroxolyn®), and hydrochlorothiazide,triamterene (commercially available as Dyazide®).

Agents useful herein may also include treatment for emphysema, such astiotropium bromide (commercially available as Spiriva®); fibromyalgiamedication, such as milnacipran hydrochloride (commercially available asSavella®); medication for the treatment of gout, such as colchicine(commercially available as Colcrys®), and febuxostat (commerciallyavailable as Uloric®); enema treatments, including aminosalicylic acid(commercially available as Mesalamine® and Rowasa®); epilepsymedications, including valproic acid (commercially available asDepakene®), felbamate (commercially available as Felbatol®), lamotrigine(commercially available as Lamictal®), primidone (commercially availableas Mysoline®), oxcarbazepine (commercially available as Trileptal®),zonisamide (commercially available as Zonegran®), levetiracetam(commercially available as Keppra®), and phenytoin sodium (commerciallyavailable as Dilantin®).

Erectile dysfunction therapies useful herein include, but are notlimited to, drugs for facilitating blood flow to the penis, and foreffecting autonomic nervous activities, such as increasingparasympathetic (cholinergic) and decreasing sympathetic (adrenersic)activities. Useful agents for treatment of erectile dysfunction include,for example, those agents available as alprostadil (commerciallyavailable as Caverject®), tadalafil (commercially available as Cialis®),vardenafil (commercially available as Levitra®), apomorphine(commercially available as Uprima®), yohimbine hydrochloride(commercially available as Aphrodyne®, Yocon®), and sildenafil citrate(commercially available as Viagra®).

Agents useful herein may further include eye medications and treatment,such as dipivefrin hydrochloride (commercially available as Propine®),valganciclovir (commercially available as Valcyte®), ganciclovirophthalmic gel (commercially available as Zirgan®); bepotastine besilate(commercially available as Bepreve®), besifloxacin (commerciallyavailable as Besivance®), bromfenac (commercially available as Xibrom®),fluorometholone (commercially available as FML®), pilocarpinehydrochloride (commercially available as Pilocar®), cyclosporine(commercially available as Restasis®), brimonidine tartrate(commercially available as Alphagan P®), dorzolamidehydrochloride/timolol maleate (commercially available as Cosopt®),bimatoprost (commercially available as Lumigan®), timolol maleate(available as Timoptic®), travoprost (commercially available asTravatan®), latanoprost (commercially available as Xalatan®),echothiophate iodide (commercially available as Phospholine Iodide®),and ranibizumab (commercially available as Lucentis®); fluidcontrollers, such as acetazolamide (commercially available as Diamox®);gallstone medications, including ursodiol (commercially available asActigall®); medication for the treatment of gingivitis, includingchlorhexidine gluconate (commercially available as Peridex®); headachemedications, including butalbital/codeine phosphate/aspirin/caffeine(commercially available as Fiornal® with Codeine), naratriptanhydrochloride (commercially available as Amerge®), almotriptan(commercially available as Axert®), ergotamine tartrate/caffeine(commercially available as Cafergot®), butalbital/acetaminophen/caffeine(commercially available as Fioricet®), butalbital/aspirin/caffeine(commercially available as Fiorinal®), frovatriptan succinate(commercially available as Frova®), rizatriptan benzoate (commerciallyavailable as Maxalt®), isometheptenemucate/dichloralphenazone/acetaminophen (commercially available asMidrin®), dihydroergotamine mesylate (commercially available asMigranal®), eletriptan hydrobromide (commercially available as Relpax®),and zolmitriptan (commercially available as Zomig®); influenzamedication, such as haemophilus b conjugate vaccine; tetanus toxoidconjugate (commercially available as Hiberix®); and heart treatments,including quinidine sulfate, isosorbide dinitrate/hydralazinehydrochloride (commercially available as BiDil®), digoxin (commerciallyavailable as Lanoxin®), flecainide acetate (commercially available asTambocor®), mexiletine hydrochloride (commercially available asMexitil®), disopyramide phosphate (commercially available as Norpace®),procainamide hydrochloride (commercially available as Procanbid®), andpropafenone (commercially available as Rythmol®).

Other useful agents include hepatitis treatments, including entecavir(commercially available as Baraclude®), hepatitis B immune globulin(commercially available as HepaGam B®), andcopegus/rebetol/ribasphere/vilona/virazole (commercially available asRibavirin®); herpes treatments, including valacyclovir hydrochloride(commercially available as Valtrex®), penciclovir (commerciallyavailable as Denavir®), acyclovir (commercially available as Zovirax®),and famciclovir (commercially available as Famvir®); treatment for highblood pressure, including enalaprilat (available as Vasotec®), captopril(available as Capoten®) and lisinopril (available as Zestril®),verapamil hydrochloride (available as Calan®), ramipril (commerciallyavailable as Altace®), olmesartan medoxomil (commercially available asBenicar®), amlodipine/atorvastatin (commercially available as Caduet®),nicardipine hydrochloride (commercially available as Cardene®),diltiazem hydrochloride (commercially available as Cardizem®), quinaprilhydrochloride (commercially available as Accupril®), quinaprilhydrochloride/hydrochlorothiazide (commercially available asAccuretic®), perindopril erbumine (commercially available as Aceon®),candesartan cilexetil (commercially available as Atacand®), candesartancilexetil/hydrochlorothiazide (commercially available as Atacand HCT®),irbesartan/hydrochlorothiazide (commercially available as Avalide®),irbesartan (commercially available as Avapro®), amlodipinebesylate/olmesartan medoxomil (commercially available as Azor®),levobunolol hydrochloride (commercially available as Betagan®),betaxolol hydrochloride (commercially available as Betoptic®), nebivolol(commercially available as Bystolic®), captopril/hydrochlorothiazide(commercially available as Capozide®), doxazosin mesylate (commerciallyavailable as Cardura®), clonidine hydrochloride (commercially availableas Catapres®), carvedilol (commercially available as Coreg®), nadolol(commercially available as Corgard®), nadolol/bendroflumethiazide(commercially available as Corzide®), valsartan (commercially availableas Diovan®), isradipine (commercially available as DynaCirc®), Guanabenzacetate. (commercially available as Wytensin®), Guanfacine hydrochloride(commercially available as Tenex® or Intuniv®), losartanpotassium/hydrochlorothiazide (commercially available as Hyzaar®),propranolol hydrochloride (commercially available as Indera®),propranolol hydrochloride/hydrochlorothiazide (commercially available asInderide®), eplerenone (commercially available as Inspra®), ambrisentan(commercially available as Letairis®), enalapril maleate/felodipine(commercially available as Lexxel®), metoprolol tartrate (commerciallyavailable as Lopressor®), benazepril hydrochloride (commerciallyavailable as Lotensin®), benazepril hydrochloride/hydrochlorothiazide(commercially available as Lotensin HCT®), amlodipine/benazeprilhydrochloride (commercially available as Lotrel®), indapamide(commercially available as Lozol®), trandolapril (commercially availableas Mavik®), telmisartan (commercially available as Micardis®),telmisartan/hydrochlorothiazide (commercially available as MicardisHCT®), prazosin hydrochloride (commercially available as Minipress®),amiloride, hydrochlorothiazide (commercially available as Moduretic®),fosinopril sodium (commercially available as ZZXT Monopril®), fosinoprilsodium/hydrochlorothiazide (commercially available as Monopril-HCT®),pindolol (commercially available as Visken®), felodipine (commerciallyavailable as Plendil®), sildenafil citrate (commercially available asRevatio®), Nisoldipine (commercially available as Sular®),trandolapril/verapamil hydrochloride (commercially available as Tarka®),aliskiren (commercially available as Tekturna®), eprosartan mesylate(commercially available as Teveten®), eprosartanmesylate/hydrochlorothiazide (commercially available as Teveten HCT®),moexipril hydrochloride/hydrochlorothiazide (commercially available asUniretic®), moexipril hydrochloride (commercially available asUnivasc®), enalapril maleate/hydrochlorothiazide (commercially availableas Vaseretic®), and lisinopril/hydrochlorothiazide (commerciallyavailable as Zestoretic®).

The present invention may include agents useful in the medication forthe treatment of HIV/AIDS, such as amprenavir (commercially available asAgenerase®), tipranavir (commercially available as Aptivus®),efavirenz/emtricitabine/tenofovir (commercially available as Atripla®),lamivudine/zidovudine (commercially available as Combivir®), indinavirsulfate (commercially available as Crixivan®), lamivudine (commerciallyavailable as Epivir®), saquinavir (commercially available asFortovase®), zalcitabine (commercially available as Hivid®),lopinavir/ritonavir (commercially available as Kaletra®), fosamprenavircalcium (commercially available as Lexiva®), ritonavir (commerciallyavailable as Norvir®), zidovudine (commercially available as Retrovir®),atazanavir sulfate (commercially available as Reyataz®), efavirenz(commercially available as Sustiva®), abacavir/lamivudine/zidovudine(commercially available as Trizivir®), didanosine (commerciallyavailable as Videx®), nelfinavir mesylate (commercially available asViracept®), nevirapine (commercially available as Viramune®), tenofovirdisoproxil fumarate (commercially available as Viread®), stavudine(commercially available as Zerit®), and abacavir sulfate (commerciallyavailable as Ziagen®); homocysteiene removers, including betaineanhydrous (commercially available as Cystadane®); medications, such asinsulin (commercially available as Apidra®, Humalog®, Humulin®, Iletin®,and Novolin®); and HPV treatment, such as Human papillomavirus vaccine(commercially available as Gardasil®) or human papillomavirus bivalent(commercially available as Cervarix®); immunosuppressants, includingcyclosporine (commercially available as Gengraf®, Neoral®, Sandimmune®,and Apo-Cyclosporine®).

Agents useful in the present invention may further include prolactininhibitors, such as bromocriptine mesylate (commercially available asParlodel®); medications for aiding in stress tests, such as regadenoson(commercially available as Lexiscan®); baldness medication, includingfinasteride (commercially available as Propecia® and Proscar®);pancreatitis treatment, such as gemfibrozil (commercially available asLopid®); hormone medications, such as norethindrone acetate/ethinylestradiol (commercially available as femHRT®), goserelin acetate(commercially available as Zoladex®), progesterone gel (commerciallyavailable as Prochieve®), progesterone (commercially available asPrometrium®), calcitonin-salmon (commercially available as Miacalcin®),calcitriol (commercially available as Rocaltrol®), Synthroid(commercially available as Levothroid®, Levoxyl®, Unithroid®),testosterone (commercially available as Testopel®, Androderm®,Testoderm®, and AndroGel®); menopause medication, such asestradiol/norethindrone acetate (commercially available as Activella®),drospirenone/estradiol (commercially available as Angeliq®),estradiol/levonorgestrel (commercially available as Climara Pro®),estradiol/norethindrone acetate (commercially available as CombiPatch®),estradiol (commercially available as Estrasorb®, Vagifem® andEstroGel®), esterified estrogens and methyltestosterone (commerciallyavailable as Estratest®), estrogen (commercially available as Alora®,Climara®, Esclim®, Estraderm®, Vivelle®, Vivelle-Dot®), estropipate(commercially available as Ogen®), conjugated estrogens (commerciallyavailable as Premarin®), and medroxyprogesterone acetate (commerciallyavailable as Provera®); menstrual medications, including leuprolideacetate (commercially available as Lupron Depot), tranexamic acid(commercially available as Lysteda®), and norethindrone acetate(commercially available as Aygestin®); and muscle relaxants, includingcyclobenzaprine hydrochloride (commercially available as Flexeril®),tizanidine (commercially available as Zanaflex®), and hyoscyaminesulfate (commercially available as Levsin®).

Agents useful herein may also include osteoporosis medications,including ibrandronate sodium (commercially available as Boniva®),risedronate (commercially available as Actonel®), raloxifenehydrochloride (commercially available as Evista®, Fortical®), andalendronate sodium (commercially available as Fosamax®); ovulationenhancers, including clomiphene citrate (commercially available asSerophene®, Clomid®, Serophene®); Paget's disease treatment, such asetidronate disodium (commercially available as Didronel®); pancreaticenzyme deficiency medications, such as pancrelipase (commerciallyavailable as Pancrease® or Zenpep®); medication for the treatment ofParkinson's disease, such as pramipexole dihydrochloride (commerciallyavailable as Mirapex®), ropinirole hydrochloride (commercially availableas Requip®), carbidopa/levodopa (commercially available as Sinemet CRC),carbidopa/levodopa/entacapone (commercially available as Stalevo®),selegiline hydrochloride (commercially available as Zelapar®),rasagiline (commercially available as Azilect®), entacapone(commercially available as Comtan®), and selegiline hydrochloride(commercially available as Eldepryl®); multiple sclerosis medication,such as dalfampridine (commercially available as Ampyra®) and interferonbeta-I b (commercially available as Extavia®); prostate medication,including flutamide (commercially available as Eulexin®), nilutamide(commercially available as Nilandron®), dutasteride (commerciallyavailable as Avodart®), tamsulosin hydrochloride (commercially availableas Flomax®), terazosin hydrochloride (commercially available asHytrin®), and alfuzosin hydrochloride (commercially available asUroXatral®).

Films of the present invention may further include psychiatricmedications, including alprazolam (available as Niravam®, Xanax®),clozopin (available as Clozaril®), haloperidol (available as Haldol®),fluoxetine hydrochloride (available as Prozac®), sertralinehydrochloride (available as Zoloft®), asenapine (commercially availableas Saphris®), iloperidone (commercially available as Fanapt®), paroxtinehydrochloride (available as Paxil®), aripiprazole (commercially aavialbeas Abilify®), guanfacine (commercially available as Intuniv®),Amphetamines and methamphetamines (commercially available as Adderall®and Desoxyn®), clomipramine hydrochloride (commercially available asAnafranil®), Buspirone hydrochloride (commercially available asBuSpar®), citalopram hydrobromide (commercially available as Celexa®),duloxetine hydrochloride (commercially available as Cymbalta®),methylphenidate (commercially available as Ritalin, Daytrana®),divalproex sodium (Valproic acid) (commercially available as Depakote®),dextroamphetamine sulfate (commercially available as Dexedrine®),venlafaxine hydrochloride (commercially available as Effexor®),selegiline (commercially available as Emsam®), carbamazepine(commercially available as Equetro®), lithium carbonate (commerciallyavailable as Eskalith®), fluvoxamine maleate/dexmethylphenidatehydrochloride (commercially available as Focalin®), ziprasidonehydrochloride (commercially available as Geodon®), ergoloid mesylates(commercially available as Hydergine®), escitalopram oxalate(commercially available as Lexapro®), chlordiazepoxide (commerciallyavailable as Librium®), molindone hydrochloride (commercially availableas Moban®), phenelzine sulfate (commercially available as Nardil®),thiothixene (commercially available as Navane®), desipraminehydrochloride (commercially available as Norpramin®), benzodiazepines(such as those available as Oxazepam®), nortriptyline hydrochloride(commercially available as Pamelor®), tranylcypromine sulfate(commercially available as Parnate®), prochlorperazine, mirtazapine(commercially available as Remeron®), risperidone (commerciallyavailable as Risperdal®), quetiapine fumarate (commercially available asSeroquel®), doxepin hydrochloride (commercially available as Sinequan®),atomoxetine hydrochloride (commercially available as Strattera®),trimipramine maleate (commercially available as Surmontil®),olanzapine/fluoxetine hydrochloride (commercially available asSymbyax®), imipramine hydrochloride (commercially available asTofranil®), protriptyline hydrochloride (commercially available asVivactil®), bupropion hydrochloride (commercially available asWellbutrin®, Wellbutrin SR®), and Wellbutrin XR®), and olanzapine(commercially available as Zyprexa®).

Agents useful herein may also include uric acid reduction treatment,including allopurinol (commercially available as Zyloprim®); seizuremedications, including gabapentin (commercially available asNeurontin®), ethotoin (commercially available as Peganone®), vigabatrin(commercially available as Sabril®), and topiramate (commerciallyavailable as Topamax®); treatment for shingles, such as zoster vaccinelive (commercially available as Zostavax®); skin care medications,including calcipotriene (commercially available as Dovonex®),ustekinumab (commercially available as Stelara®), televancin(commercially available as Vibativ®), isotretinoin (commerciallyavailable as Accutane®), hydrocortisone/iodoquinol (commerciallyavailable as Alcortin®), sulfacetamide sodium/sulfur (commerciallyavailable as Avar®), azelaic acid (commercially available as Azelex®,Finacea®), benzoyl peroxide (commercially available as Desquam-E®),adapalene (commercially available as Differin®), fluorouracil(commercially available as Efudex®), pimecrolimus (commerciallyavailable as Elidel®), topical erythromycin (commercially available asA/T/S®, Erycette®, T-Stat®), hydrocortisone (commercially available asCetacort®, Hytone®, Nutracort®), metronidazole (commercially availableas MetroGel®), doxycycline (commercially available as Oracea®),tretinoin (commercially available as Retin-A® and Renova®),mequinol/tretinoin (commercially available as Solage®), acitretin(commercially available as Soriatane®), calcipotrienehydrate/betamethasone dipropionate (commercially available asTaclonex®), tazarotene (commercially available as Tazorac®),fluocinonide (commercially available as Vanos®), desonide (commerciallyavailable as Verdeso®), miconazole nitrate/Zinc oxide (commerciallyavailable as Vusion®), ketoconazole (commercially available asXolegel®), and efalizumab (commercially available as Raptiva®).

Other agents useful herein may include Sleep disorder medications,including zaleplon (available as Sonata®), eszopiclone (available asLunesta®), zolpidem tartrate (commercially available as Ambien®, AmbienCR®, Edluar®), lorazepam (commercially available as Ativan®), flurazepamhydrochloride (commercially available as Dalmane®), triazolam(commercially available as Halcion®), clonazepam (commercially availableas Klonopin®), barbituates, such as Phenobarbital®), Modafinil(commercially available as Provigil®), temazepam (commercially availableas Restoril®), ramelteon (commercially available as Rozerem®),clorazepate dipotassium (commercially available as Tranxene®), diazepam(commercially available as Valium®), quazepam (commercially available asDoral®), and estazolam (commercially available as ProSom®); smokingcessation medications, such as varenicline (commercially available asChantix®), nicotine, such as Nicotrol®, and bupropion hydrochloride(commercially available as Zyban®); and steroids, includingalclometasone dipropionate (commercially available as Aclovate®),betamethasone dipropionate (commercially available as Diprolene®),mometasone furoate (commercially available as Elocon®), fluticasone(commercially available as Flonase®, Flovent®, Flovent Diskus®, FloventRotadisk®), fluocinonide (commercially available as Lidex®), mometasonefuroate monohydrate (commercially available as Nasonex®), desoximetasone(commercially available as Topicort®), clotrimazole/betamethasonedipropionate (commercially available as Lotrisone®), prednisoloneacetate (commercially available as Pred Forte®, Prednisone®, BudesonidePulmicort®, Rhinocort Aqua®), prednisolone sodium phosphate(commercially available as Pediapred®), desonide (commercially availableas Tridesilon®), and halobetasol propionate (commercially available asUltravate®).

Films of the present invention may further include agents useful forthyroid disease treatment, such as hormones TC and TD (commerciallyavailable as Armour Thyroid®); potassium deficiency treatment, includingpotassium chloride (commercially available as Micro-K®); triglyceridesregulators, including omega-3-acid ethyl esters (commercially availableas Omacor®); urinary medication, such as phenazopyridine hydrochloride(commercially available as Pyridium®) and methenamine, methyleneblue/phenyl salicylate/benzoic acid/atropine sulfate/hyoscyamine(commercially available as Urised®); prenatal vitamins (commerciallyavailable as Advanced Natalcare®, Materna®, Natalins®, PrenateAdvance®); weight control medication, including orlistat (commerciallyavailable as Xenical®) and sibutramine hydrochloride (commerciallyavailable as Meridia®).

The popular H₂-antagonists which are contemplated for use in the presentinvention include cimetidine, ranitidine hydrochloride, famotidine,nizatidien, ebrotidine, mifentidine, roxatidine, pisatidine andaceroxatidine.

Active antacid ingredients include, but are not limited to, thefollowing: aluminum hydroxide, dihydroxyaluminum aminoacetate,aminoacetic acid, aluminum phosphate, dihydroxyaluminum sodiumcarbonate, bicarbonate, bismuth aluminate, bismuth carbonate, bismuthsubcarbonate, bismuth subgallate, bismuth subnitrate, bismuthsubsilysilate, calcium carbonate, calcium phosphate, citrate ion (acidor salt), amino acetic acid, hydrate magnesium aluminate sulfate,magaldrate, magnesium aluminosilicate, magnesium carbonate, magnesiumglycinate, magnesium hydroxide, magnesium oxide, magnesium trisilicate,milk solids, aluminum mono-ordibasic calcium phosphate, tricalciumphosphate, potassium bicarbonate, sodium tartrate, sodium bicarbonate,magnesium aluminosilicates, tartaric acids and salts.

The pharmaceutically active agents employed in the present invention mayinclude allergens or antigens, such as, but not limited to, plantpollens from grasses, trees, or ragweed; animal danders, which are tinyscales shed from the skin and hair of cats and other furred animals;insects, such as house dust mites, bees, and wasps; and drugs, such aspenicillin.

In one particular method of forming a film, a wet film matrix isdeposited onto the surface of a substrate. Any desired substrate may beused, including, for example, mylar, paper, plastic, metal, foil, andcombinations thereof. The substrate may be laminated if desired.Further, the substrate may be chemically treated on one or more surfacesprior to depositing the wet film matrix thereon. Desirably, thesubstrate is substantially flat, but is flexible to allow for rolling,such as for storage or for packaging of the formed film products. Thesubstrate may include one or more dams, such as that disclosed inApplicant's co-pending U.S. patent application Ser. No. 12/711,883,filed Feb. 24, 2010, the entire contents of which are incorporated byreference herein. In some embodiments, the substrate may include apre-formed sheet of dissolvable and/or ingestible film, where the wetfilm-forming matrix is deposited onto the sheet, providing amulti-layered film product. In still other embodiments, the substratemay include a plurality of pre-formed film products on its surface, andthe wet film matrix is deposited onto the surface of the pre-formed filmproducts.

The substrate may have any length and width desired, depending on thesize of the apparatus used to process the film. The length of thesubstrate is not critical, since the substrate may generally be fed intothe film-forming apparatus on a continuous basis and sized by the useraccordingly. The width of the substrate is sized to be fed into theapparatus used, and may vary as desired. The width of the substratetypically determines the width of the film product that can be preparedon that substrate. For example, a plurality of film strips or individualfilm products may be prepared on the substrate, arranged in asubstantially side-by-side manner, and the cumulative width of thosefilm strips or products dictates the desired width of the substrate. Itis typical then that the batch size determines the cumulative width ofthe film, which in turn determines the optimum width of the substrate.The width of the individual film strips or products may be relativelysmall, for example, ranging from about 2 mm to about 30 mm. The width ofindividual film strips may be from about 2 mm to about 10 mm, or fromabout 10 mm to about 20 mm. It may, in some instances, be desired thatthe individual film strips include a width that is greater than 30 mm.It should be understood that the “width of the individual film strips”is intended to be an average width, and there may be some variationbetween individual film strips formed via the present invention.

There may be deposited on the substrate any number of individual filmstrips or products. In some embodiments, there may be deposited betweenabout 2 to about 30 individual film strips or products on a substrate,the film strips or products arranged in a substantially side-by-sidefashion with a gap separating adjacent film strips. In some embodiments,there may be between about 10 to about 20 individual film strips orproducts on a substrate. It may be desired, for example, during a testrun or other experimental procedure, that only one film strip or productbe deposited on the substrate. Desirably, the width of the substrate isat least 1 inch wider than the cumulative width of the dried film stripsor products and any gaps therebetween. Having a substrate wider than thecumulative width of the dried film strips or products and gapstherebetween is useful in processing the product(s), as it allows sometolerance during the process.

In use, a wet film-forming matrix is deposited onto the top surface ofthe substrate, as will be described in further detail below. In apreferred embodiment, the wet matrix is deposited onto the substrate viaextrusion, however, the wet matrix may be deposited onto the substratevia any means desired, including coating, casting, spraying, or othermeans. The wet matrix may be deposited in one continuous strip orstripe, which results in a dried film stripe, and which is then capableof being cut into several smaller individual dosages. Alternatively, thewet matrix may be deposited in discrete amounts, such that the depositedwet matrix has a width and length that is capable of being dried to forman individual film product having the desired width and length.

Once deposited on the surface of the substrate, the deposited wet matrixmay be dried through any desired drying means, including but not limitedto those methods set forth in the patents and applications previouslyincorporated by reference above. For example, the film matrix may berapidly dried in an oven so as to provide a viscoelastic mass within thefirst about 0.5 to about 4.0 minutes, thus “locking in” the componentsof the film forming matrix. The resulting viscoelastic mass may then befurther dried to provide the final film product. One benefit of drying afilm product on the surface of a substrate is that the film may be driedquickly and efficiently, resulting in a film that has a substantiallyflat form. Further, the film may become adhered to the surface of thesubstrate during drying, which aids in packaging and dispensing the endproduct. If desired, the resulting dried film product and the substrateupon which it has been deposited may be die cut and packaged together,thereby minimizing the requirement to remove the film product from thesubstrate prior to packaging. It may be desirable, for example, for thefilm product to remain adhered to the substrate, and the filmproduct/substrate product be provided to an end user. For example, thepresent method may be useful in forming a continuous stripe of filmproduct, which may be rolled and dispensed through an apparatus such asthat described in Applicant's co-pending application, U.S. patentapplication Ser. No. 12/711,899, filed on Feb. 24, 2010, entitled“Device And System For Determining, Preparing And AdministeringTherapeutically Effective Doses”, the entire contents of which areincorporated herein by reference.

With reference to the Figures, the present invention provides a systemand method for efficiently and continuously producing film products,especially individual film products or film stripes, with minimal waste.The film products formed through the present invention provide highcontent uniformity and therefore provide film products having highlyaccurate dosages. In one embodiment set forth in FIG. 1, a film formingapparatus 10 is provided. The film forming apparatus 10 includes asubstrate 20. As explained above, the substrate may be formed from anydesired materials, including, for example, mylar, paper, plastic, metal,foil, and combinations thereof. The substrate 20 may be laminated ifdesired. Further, the substrate 20 may be chemically treated prior todepositing a wet film matrix thereon. Desirably, the substrate 20 issubstantially flat, but is flexible to allow for rolling.

In some embodiments, the substrate 20 may include a pre-formed sheet offilm (such as an ingestible film or other biocompatible film productthat may be applied to one or more body surfaces). The pre-formed sheetof film may be self-supporting and fed through the apparatus, or it maybe pre-formed onto another substrate, whereby both are fed through theapparatus. The substrate 20 includes a top surface and a bottom surface(not shown). In this embodiment, a wet film matrix is capable of beingdeposited onto the top surface of the substrate 20. In embodiments wherethe substrate 20 is a pre-formed sheet of film, the deposition of a wetfilm forming matrix thereon provides a multi-layered film product, wherethe pre-formed film is a first layer (or “backing layer”), and thedeposited film forming matrix forms a second layer (or “active layer”).It may be useful that the first layer not include an active, while thesecond layer includes an active, although both layers may include anactive. The resulting multi-layered film may then be sized and cut toprovide individual multi-layered film products.

In still other embodiments, the substrate 20 may be a sheet of anon-ingestible product (i.e., paper, mylar, etc.), which includes on itstop surface a plurality of pre-formed ingestible film products formedthereon. In this embodiment, a wet film matrix may be deposited onto thetop surface of the pre-formed film products. This embodiment forms amulti-layered film product without the need for further sizing orcutting the multi-layered film products. In further embodiments,described in further detail below, the apparatus 10 may include a meansfor forming a first layer of film product on the top surface of thesubstrate 20 prior to depositing a second layer (or layers) of filmproduct onto the deposited first layer of film product.

The substrate 20 may be stored as a continuous roll of substrate 20prior to use. In use, the first end (not shown) of the substrate 20 isfed into the apparatus 10 in the direction designated by arrow A. Duringuse, the substrate 20 may continuously travel in the direction A, duringwhich time a wet film matrix is deposited onto the top surface ofsubstrate 20, and led along the direction A during the drying process,as will be described in further detail below. The substrate 20 maytravel at any desired rate of speed. The rate at which the substrate 20travels may be altered as necessary to suit the drying needs of thefilm-forming material in view of the desired oven temperature. Forexample, if a longer drying time is desired, the substrate 20 may travelat a slower rate of speed through the apparatus 10. If a shorter dryingtime is required, the substrate 20 may travel at a higher rate of speedthrough the apparatus 10. In addition, in some embodiments, the rate ofspeed may control the thickness of the wet film products depositedthereon. For example, in an extrusion process, a faster rate of speed ofthe substrate 20 may result in a thinner wet film product depositedthereon, and vice versa.

The substrate 20 may be any desired length or width, as explained above.Desirably, the width of the substrate 20 is sufficient to allow thedeposition of a plurality of individual film products arranged in asubstantially side-by-side pattern. For example, the substrate 20 may bewide enough to allow deposition of between about 2 to about 30individual film products, arranged substantially side-by-side. Theindividual film products may have a gap between adjacent film strips, soas to allow for easier processing and distribution.

The apparatus 10 includes a reservoir 30, designed to house apredetermined amount of film forming matrix. The film forming matrixincludes any desired film forming components, including, for example,polymers, solvents, sweeteners, active agents, fillers, and the like.Useful components for a film forming matrix include those disclosed inU.S. Publication No. 2005/0037055, the contents of which areincorporated by reference herein in entirety. The reservoir 30 mayinclude more than one separate housings or compartments to store thevarious components of the film forming matrix. For example, it may bedesired to store the active component in a separate container thansolvents or polymers until immediately prior to deposition onto thesubstrate 20. The reservoir 30 is preferably pressurized, such that itmay effectively force the film forming matrix housed therein through theapparatus 10.

In some embodiments, the apparatus 10 is capable of extruding a filmforming matrix, as will be explained in further detail below. In suchembodiments, it may be desired that the film forming matrix have a highviscosity and/or a high solids content. For example, the film formingmatrix may include at least 30% solids content, or it may include atleast 25% solids content, or alternatively, it may include at least 20%solids content. In other embodiments, the matrix may be a slurry orsuspension of solids in a fluid carrier. The apparatus 10 and methodsdescribed herein allows for processing of such a film forming matrixhaving a high solid content without fear of clogs or blockages in thesystem. Alternatively, the film forming matrix may have a low solidcontent, and may have a lower viscosity, if desired. It is preferablethat the film-forming matrix have a sufficient viscosity so as togenerally maintain its shape upon disposition onto the surface of thesubstrate 20.

Attached to the reservoir 30 is a feed line or tube 40, which is influid connection with the reservoir 30 and connects the reservoir 30 toa plurality of volumetric pumps 50, 50′. The feed line 40 may be made ofany desired material, and may have any thickness or radius desired. Itis preferable that the feed line 40 have a sufficient radius so as toeffectively transport the film forming matrix from the reservoir 30 tothe volumetric pumps 50 without blockage, clogging, or exhibiting asufficient pressure drop as to insufficiently supply material to thepumps. The apparatus 10 may include any number of volumetric pumps 50desired, depending upon the number of individual film products that theuser wishes to produce. In one embodiment, each volumetric pump 50 inthe apparatus 10 will be used to form film products, and thus the numberof volumetric pumps 50 used may dictate the number of film productsformed. The volumetric pumps 50 are desirably arranged in a side-by-sidepattern in the apparatus 10. The feed line 40 desirably feeds the filmforming matrix from the reservoir 30 to the volumetric pumps 50 in aparallel fashion, thus allowing each volumetric pump 50 to be fed withthe film forming matrix on a substantially equal basis.

The volumetric pumps 50 may be any type of pumping apparatus desired bythe user. Desirably, the volumetric pumps 50 are each of approximatelyequal size and shape, and are capable of dispensing substantially thesame amount of film forming matrix therefrom. It is particularly desiredto use a pump 50 that is capable of dispensing a known amount of matrixper each pumping cycle. Further, the pump 50 should be capable of beingre-filled with film forming matrix after a pre-determined amount of filmforming matrix has been dispensed via pumping. In particular, it isdesired that the pump 50 be re-filled with substantially the same amountof film-forming matrix after each pumping cycle. Thus, each pumpingcycle (which includes one dispensing of film forming matrix and onere-filling of film forming matrix) should include a substantiallyconstant amount of film forming matrix. As can be understood, regardlessof the type of pump used, it is important that the pumps 50 provide anaccurate and consistent dispense of the wet film matrix, so as to ensuresubstantial uniformity between and among each of the resulting filmproducts.

In one embodiment, the volumetric pumps 50 are piston pumps. If desired,the volumetric pumps 50 may include dual piston pumps, where, as thepump 50 dispenses the volume of film-forming matrix, the pump 50concurrently is re-filled with another volume of film-forming matrix. Inother embodiments, the volumetric pumps 50 may include gear pumps. Forformation of film-containing patches, dual piston pumps are particularlydesired. The apparatus 10 may include a combination of at least onepiston pump, at least one dual piston pump, at least one gear pump, andcombinations thereof. Piston pumps and dual piston pumps are especiallypreferred, since such pumps have “suck back” capability and are thusable to prevent or reduce the amount of drool after the wet film matrixhas been pumped therefrom. Further, piston pumps and dual piston pumpsprovide the ability to continuously load and extrude the wet filmforming matrix as the substrate 20 moves. These pumps are efficient andfurther avoid the requirement of having a head manifold move back andforth, as in typical systems.

In some embodiments, the volumetric pumps 50 may have variable strokeand/or variable speed settings. That is, the volumetric pumps 50 mayhave a variable stroke, allowing the user to be able to change thestroke associated with the pump 50 to suit the particular needs. In someembodiments, the volumetric pumps 50 may dispense anywhere from about 4microliters per stroke to about 100 microliters per stroke. Further, thevolumetric pumps 50 may be variable speed pumps, to allow the user toset the particular speed desired for the particular film product beingformed. For example, if a longer drying time is desired by the user, thevolumetric pump 50 may be set to a slower dispensing speed, allowing fora longer process and thus a longer drying time. Alternatively, for ashorter drying time, a higher speed pump may be desired. The speed andstroke of the volumetric pumps 50 may be related to the speed at whichthe substrate 20 travels through the apparatus 10.

The volumetric pumps 50 used herein should be sized appropriately toprovide the desired film volume. In particular, the volumetric pumps 50should be sized to fill and dispense sufficient amount of film formingmatrix to form one individual film product having the desired volume.For example, in one embodiment, the desired resultant dried individualfilm product may be about 1 mg to about 20 mg in total weight. In someembodiments, the dried individual film product may be 60 mg in totalweight or less. It is to be understood that the weight of a wet filmproduct will be higher than the resulting dried film product, due toloss of certain volatiles. The volumetric pumps 50 should be capable ofdispensing about 3 microliters to about 250 microliters per pumpingcycle, or alternatively 250 microliters or less per pumping cycle. Fortransdermal systems, the desired resultant individual dried film productmay be about 10 mg to about 2000 mg in total weight. Thus, thevolumetric pumps 50 should be capable of dispensing about 30 microlitersto about 10 milliliters per pumping cycle to provide the desiredresulting dried film weight.

In another embodiment, the volumetric pump 50 can be a positivedisplacement pump. Examples include a progressive cavity pump also knownas a progressing cavity pump, eccentric screw pump or even just cavitypump. One specific example of this type of pump is the Moyno® pump(manufactured by Moyno, Inc.). Additional positive displacement pumpsinclude gear pumps, rotary lobe pumps, piston pumps, diaphragm pumps,screw pumps, hydraulic pumps, vane pumps, regenerative (peripheral)pumps and peristaltic pumps. Systems of the present invention mayinclude one or more than one of the aforementioned volumetric pumps 50.

Each of the volumetric pumps 50 is desirably associated with a coatinghead manifold 60, which includes a plurality of orifices 70, 70′.Desirably, each volumetric pump 50 is associated with one individualorifice 70. The volumetric pump 50 is in fluid communication with theorifice 70 with which it is associated, thus allowing the film formingmatrix to be pumped from the pump 50 through the orifice 70. In oneparticular embodiment, the orifices 70 are slot dies, but the orifices70 may be any other opening or die desired. The orifice 70 is desirablysized so as to allow the formation of the desired film product.

The orifices 70 are desirably in communication with the substrate 20,such that when a particular amount of wet film forming matrix isdispensed through the orifice 70, the wet film forming matrix isdeposited onto the top surface of the substrate 20. Thus, in oneembodiment, the manifold 60 has a first side 65A and a second side 65B,with the orifice 70 extending through the manifold 60 from the firstside 65A to the second side 65B. The pump 50 is in communication withthe first side 65A of the manifold. The wet film matrix is pumped fromthe reservoir 30, through feed line 40, through the pump 50, through theorifice 70, and deposited onto the substrate 20, which, duringoperation, is traveling in the direction A. It is particularly desirablethat the wet film matrix be extruded through the orifice 70 directlyonto the substrate 20, and thus the wet film matrix should havesufficiently high viscosity and/or solids content so as to allow forextrusion. In addition, the wet film forming matrix should have asufficient viscosity so as to generally maintain its shape and sizeafter deposition onto the surface of the substrate 20. It iscontemplated, of course, that the matrix may alternatively have a lowerviscosity, and that the matrix may be simply flowed through the orifice70 onto the substrate 20. The substrate 20 may have discrete dams, wellsor pockets formed therein, between or into which the wet film formingmatrix may be deposited.

In one embodiment, a plurality of individual wet film products 80, 80′is deposited onto the surface of the substrate 20 in a substantiallyside-by-side manner. The individual wet film products 80 are depositedonto the substrate 20 as the substrate 20 moves through the apparatus10, and preferably, each individual wet film product 80 is extruded ontoa region of the substrate 20 where no individual wet film product 80 hasalready been extruded. Thus, the substrate 20 may have a plurality ofindividual wet film products 80 deposited along its length and itswidth. Each individual wet film product 80 is sized so as to provide thedesired final dried film product. The speed at which the substrate 20travels during the deposition of the wet film product 80 thereon maydictate or control the size of the wet film product 80. In particular,the thickness of the wet film product 80 may be controlled by the speedof the substrate 20, where a faster moving substrate 20 may provide athinner wet film product 80, and vice versa.

During use, each pump 50 dispenses a plurality of individual wet filmproducts 80 onto the substrate 20 in a lane (85A, 85B, 85C). Each lane(85) includes a plurality of individual wet film products 80. Desirably,each of the individual wet film products 80 has a substantially uniformsize, shape, and content. In this fashion, the known dosage amountbetween each of the individual wet film products 80 can be known with agreat deal of accuracy. The individual wet film products 80 may bedeposited directly onto a non-film substrate 20, or the individual wetfilm products 80 may be deposited onto a substrate 20 that is apre-formed film (thus forming a multi-layered film product). It isdesired that the volumetric pumps 50 repeatedly dispense the individualwet film products 80 onto the surface of the substrate 20, so as to formthe lane 85 of individual wet film products 80.

Any number of individual wet film products 80 may be deposited onto thesurface of the substrate 20. The number of lanes 85 of wet film products80 depends upon the number of pumps 50 and orifices 70 in the apparatus10. For example, if the apparatus 10 includes five pumps 50 and orifices70 associated therewith; there will be five lanes 85 of wet filmproducts 80 formed on the substrate 20. Any number of pumps 50 andorifices 70 may be used in the apparatus 10, and desirably there may bebetween about 2 and about 30 pumps 50 and orifices 70 in the apparatus10. Therefore, there may be between about 2 and about 30 lanes 85 ofindividual wet film products 80 formed on the substrate 20. Dependingupon the speed and rate of the pump 50 and the substrate 20, there maybe any number of individual wet film products 80 per each lane 85. Asdepicted in FIG. 1, there is desirably a slight gap between eachindividual film product 80 in the lane 85, and there is a slight gapbetween each adjacent lane 85. Gaps between individual wet film products80 may aid in the processing and later packaging of the resultant filmproduct.

As explained above, the substrate 20 may include an ingestible filmproduct pre-formed thereon, where the wet film products 80 may bedeposited directly onto the top surface of the pre-formed film product.The pre-formed film product on the substrate may be a continuous sheetof film. Alternatively, in some embodiments, the substrate 20 may have aplurality of individual film products pre-formed on the surface thereof,and the wet film matrix is deposited onto the surface of the individualfilm products that have been pre-formed on the substrate 20 (so as toform multi-layered film products). In this fashion, multi-layered filmproducts may be formed with little to no cutting and sizing required, asthe multi-layered individual film products may simply be removed fromthe substrate 20 when dried.

The individual wet film products 80 may be any shape desired, includingsquare, rectangular, circular, or other desired shapes. The individualwet film products 80 may be any size desired, depending upon the size ofthe resulting dried film product desired. In some embodiments, the wetfilm products 80 may be small film products, i.e., being approximately 1mg in mass each. The individual film products 80 may be larger, ifdesired, such as between about 1 mg and 200 mg in mass per individualfilm product. The individual film products 80 may be 200 mg or less, oralternatively 100 mg or less. For transdermal systems, the individualfilm products 80 can range from about 10 mg to about 2000 mg, oralternatively 2000 mg or less, or 1000 mg or less.

As explained above, the substrate 20 moves in the direction A during themanufacturing process. The rate of speed of the substrate 20, as well asthe rate of speed of the pumps 50, determines the number of individualfilm products deposited onto the substrate 20 during the processing.After the individual film products 80 have been deposited onto thesubstrate 20, the substrate continues to move in the direction A towardsa drying apparatus 90, such as an oven. The wet film products 80 may bedried via any desired manner, such as those drying methods describedabove. After the drying process has been complete, the plurality ofdried individual film products may be removed from the substrate andpackaged for distribution. Alternatively, the substrate 20 with driedfilm products may be rolled and stored for future use.

In yet another embodiment, the dried individual film products may be diecut, along with the substrate 20, to be packaged for distribution.Particularly in embodiments where the substrate 20 includes a pre-formedfilm thereon, cutting the dried individual film products may be useful,so as to form a cut multi-layered film product. Desirably, when thedried film products are to be cut from the substrate 20, the substrate20 and any pre-formed film product thereon may not include any activecomponent. As such, the leftover material from which the individual filmproducts are cut may be discarded without wasting potentially expensivematerials, including actives.

In an alternative embodiment, depicted in FIG. 2, the apparatus 110 maybe used to form a continuous stripe or lane of film product 180. Theformation of a continuous stripe of film product 180 may be useful, forexample, in apparatuses that dispense a continuous roll of film, such asdescribed above. Further, the formation of a continuous stripe of filmproduct 180 may be beneficial for storage, packaging, and/ordistribution purposes. As with above, the wet film strip products 180are deposited onto a substrate 120, which may be a non-film substrate(i.e., mylar, paper, etc. as described above) or may include apre-formed film thereon. The substrate 120 moves through the apparatus110 as described above, in the direction marked by the arrow A.

The apparatus 110 includes a reservoir 130 as described above, which maybe pressurized. The reservoir 130 is designed to house a film formingmatrix. If desired, the reservoir 130 may include more than onecompartment, thus being capable of housing various film formingcomponents separately until just prior to formation of the filmproducts, i.e., keeping solvents and polymers separately housed fromactive components.

A feed line 140 is in connection with the reservoir 130, and connectsthe reservoir 130 to a plurality of volumetric pumps 150, 150′. Thevolumetric pumps 150 may be any pumping mechanism desired, andpreferably should be a pumping mechanism that allows for continuous andeven dispensing of a wet film matrix therefrom. By dispensing an evenand continuous amount of wet film matrix, uniform stripes of filmproduct 180 may be formed on the surface of the substrate 120. It isparticularly desired that each stripe of film product 180 include asubstantially uniform amount of content per unit area, especiallyincluding a known amount of active per unit area. Each stripe 180 shouldhave substantially the same thickness, width and viscosity, so as toprovide a substantially uniform final film product. Thus, the volumetricpumps 150 should be capable of dispensing a substantially uniform andcontinuous amount of wet film product. In a desirable embodiment,volumetric film pumps 150 are gear pumps or metering pumps. Any knowngear pumps and/or metering pumps in the art may be used.

There may be any number of volumetric pumps 150 in the apparatus 110,desirably arranged in a substantially side-by-side manner as shown inFIG. 2. Preferably, there is a space or gap between each volumetric pump150, which aids in the processing and subsequent collection andpackaging of the film products. The size of the gap between adjacentvolumetric pumps 150 should be large enough to allow for ease ofmanufacture, but need not be so large that it reduces the number ofpumps 150 available in the apparatus 110.

The number of volumetric pumps 150 dictates the number of stripes offilm product 180 formed by the apparatus 110. For example, there may bebetween about 2 to about 30 volumetric pumps 150 in the apparatus, andmore particularly between about 10 to about 20 volumetric pumps 150 inthe apparatus. Each volumetric pump 150 is in fluid communication withthe reservoir 130 via feed line 140, such that the film forming matrixis provided from the reservoir 130 to the pumps 150 on an even andcontinuous basis during operation. During operation, the amount of filmforming matrix provided to the volumetric pump 150 located closest tothe reservoir should be substantially equal to the amount of filmforming matrix provided to the volumetric pump 150 located furthest fromthe reservoir. This ensures that the resulting stripes of film product180 have substantially uniform content throughout the stripe 180.

Each volumetric pump 150 is associated with a first side 165A of amanifold 160, such that the film forming matrix may dispensed throughthe manifold 160. The manifold 160 includes a plurality of orifices 170extending therethrough. The orifices 170 extend through the manifold 160from the first side 165A to the second side 165B. In a preferredembodiment, each orifice 170 is in fluid communication with onevolumetric pump 150, such that the film forming matrix may be dispensedfrom one volumetric pump 150 through one orifice 170. Thus, the numberof orifices 170 should be equal to the number of volumetric pumps 150.In a desired embodiment, the orifices 170 are slot dies, but theorifices 170 may be any desired opening through which a wet film formingmatrix may be fed. It is further desired that each orifice 170 beapproximately the same size as each other, including approximately thesame height, width, length and shape. In this fashion, the resultingstripe of film product 180 dispensed will each have a substantiallyuniform shape, size and content.

During use, the volumetric pumps 150 each dispense a wet film formingmatrix through the manifold 160 via an orifice 170. The wet film formingmatrix is deposited from the orifice 170 directly onto the surface ofthe substrate 120. During the processing, the substrate 120 is movedalong the apparatus 110 in the direction A. It is particularly desirableto use volumetric pumps 150 that are capable of continuously dispensingthe film forming matrix during the manufacturing process, so as to forma continuous stripe of film product 180.

The speed of movement of the substrate 120, in conjunction with thedispensing rate of the volumetric pumps 150, controls the amount of wetfilm forming matrix deposited onto the surface of the substrate 120. Itmay be desired that the substrate 120 move at a slow rate, for example,if the wet film forming matrix is highly viscous. Alternatively, it maybe desired that the substrate 120 move at a faster rate, for example, ifthe wet film forming matrix is less viscous. The substrate 120 moves inthe direction A from the manifold 160 to a drying apparatus 190, such asa drying oven or other means for drying the wet film matrix. The speedof the substrate 120 and the size of the drying apparatus 190 willdictate the length of time that the wet film product 180 is dried in thedrying apparatus 190. For example, with a faster moving substrate 120and/or a shorter drying apparatus 190, the wet film product 180 will bedried for a shorter length of time than it would with a slower movingsubstrate 120 and/or a longer drying apparatus 190.

The individual stripes of wet film products 180 are desirably arrangedin columns (i.e., 185A, 185B, 185C) along the length of the surface ofthe substrate 120. It is particularly preferred that the stripes of wetfilm product 180 be arranged in a substantially side-by-side manner,with a sufficient space or gap between adjacent lane 185 to aid in theprocessing and subsequent collection/packaging of the film product.There may be as many columns 185 as is desired, with each column 185being formed by an individual volumetric pump 150 and associated orifice170. In addition, the space between each adjacent column 185 isapproximately equal to the space between adjacent orifices 170 in theapparatus 110. Each column 185 of film material is desirably acontinuously deposited lane of wet film matrix, such that, after dryingis complete, the individual column 185 of dried film product may becollected and packaged. For example, it may be desired that theindividual column 185 be removed from the substrate 120 and rolled,where it may be housed in a dispensing apparatus for use by an end user.Alternatively, the column 185 may be cut along with the substrate 120 toprovide a continuous stripe 185 of film with a substrate backing.Further, the stripe 180 of dried film may be cut into individual filmproducts of approximately equal size and shape, each individual filmproduct being one dosage unit.

In one particular embodiment as depicted in FIGS. 3A and 3B, theapparatus may be useful in forming a series of individual, multi-layeredproducts. For example, the individual multi layered products may includeactive-containing patches. The apparatus represented by FIG. 1 anddescribed above is particularly useful in forming individual,multi-layered products, such as patches. In this embodiment, thesubstrate 210 may include a sheet of ingestible and/or dissolvable film220 (also referred to herein as a “first layer”), which forms a backinglayer for an active-containing layer. In some embodiments, the sheet ofingestible film 220 may be the substrate 210, such as if the sheet ofingestible film 220 is self-supporting and capable of being fed throughthe apparatus itself. It is preferable that the first layer 220 be madeof a mucoadhesive, biocompatible, dissolvable material. It may bedesired that the first layer 220 is a slow-dissolving film sheet. By“slow-dissolving”, it is intended that the sheet 220 has a longerdissolution rate than the rate of the active-containing layer (describedbelow) adhered thereto. The first layer 220 may be formed on a separatesubstrate, such as mylar, paper, or other non-ingestible backing layerdescribed above. The first layer 220 may be pre-formed and dried, it maybe undried, or it may be partially dried. For example, the first layer220 may be a visco-elastic mass of film-forming material.

The first layer 220 has a first surface 225. During processing, asdescribed above, a plurality of individual active-containing wet filmlayers 230 (also referred to herein as a “second layer”) are depositedonto the first surface 225 of the first layer 220. Desirably, theactive-containing wet film layers 230 are made of a biocompatiblepolymeric material, which dissolves at a faster rate than the firstlayer 220. As explained above, the active-containing wet film layers 230are desirably deposited through a plurality of volumetric pumps in asubstantially side-by-side manner, with a desired gap between adjacentactive-containing wet film layers 230.

After the individual active-containing film layers 230 have beendeposited onto the first layer 220 and dried, the two layers (220, 230)should be sufficiently adhered to each other such that they do notbecome separated. The drying process alone may sufficiently adhere thetwo layers 220, 230 to each other, or there may be an adhesivecomposition applied between the first layer 220 and theactive-containing film layer 230.

Once the active-containing film layer 230 (and the first layer 220, ifnecessary) has been sufficiently dried, the first layer 220 may be sizedand cut. In one embodiment, the sheet of dissolvable film 220 is cut ina first direction 240 (between adjacent active containing film layers230) and in a second direction 250 (between adjacent active containingfilm layers 230) that is substantially perpendicular to the firstdirection 240, so as to form a series of individual multi-layeredproducts 260. As can be seen in FIG. 3B, the multi-layered product 260includes a first layer 220 and second layer 230 adhered thereto. Thefirst layer 220 is desirably slower-dissolving than the second layer230. The second layer 230 desirably includes at least one activecomponent. If desired, the first layer 220 may include at least oneactive component, which may be the same or different than the activecomponent in the second layer 230.

In one embodiment, it is preferred that the second layer 230 be sizedsmaller than the first layer 220, i.e., that the length and/or width ofthe second layer 230 be smaller than the length and/or width of thefirst layer 220 with which it is associated. In this fashion, at least aportion of the first side 225 of the first layer 220 is exposed beyondthe sides of the second layer 230. It is especially preferred that aportion of the first side 225 of the first layer 220 is exposed aroundthe entire periphery of the second layer 230. For example, as depictedin FIG. 3B, the second layer 230 may have a smaller length and widththan the first layer 220, and the second layer may be depositedgenerally in the center of the first layer 220. Thus, the first side 225of the first layer 220 is exposed around the entire periphery of thesecond layer 230. Alternatively, the width and/or length of the firstlayer 220 and second layer 230 may be approximately equal. In anotherembodiment, one or more sides of the first layer 220 and second layer230 may be flush with each other.

It is preferable that at least the first side 225 of the first layer 220be made of a mucoadhesive material, such that it may be sufficientlyapplied to a mucosal surface of the body of the user and adhere thereto.For example, the resulting multi-layer product 260 may be applied to anyskin surface of a user, such as, for example, a mucosal surface,including oral, nasal, optical, vaginal, or anal surfaces of the user,or may be applied to an internal body organ such as during surgery. Inthis embodiment, the individual multi-layered product 260 may be appliedby a user to a skin surface, such that the first side 225 of the firstlayer 220 is in contact with the skin surface and substantially adheredthereto. In this embodiment, the active-containing layer 230 is directedtowards the skin surface of the user. If the second layer 230 dissolvesat a faster rate than the first layer 220, the second layer 230 may beallowed to fully dissolve in the direction of the skin surface of theuser, allowing full absorption of any active(s) contained in the secondlayer 230 into the user's body.

It will be understood, of course, that the multi-layered film productembodiment described above may be formed with a continuous stripe ofactive-containing film product (as depicted in FIG. 2 and describedabove), as opposed to individual active-containing film layers 230. Insuch an embodiment, the product may be cut in such a fashion such thattwo opposing sides of the first surface 225 of the first layer 220 areexposed beyond the stripe of second layer.

In another embodiment depicted in FIG. 4, the apparatus 310 may includea first film-forming region 310A and a second film-forming region 310B.In such embodiments, the first film forming region 310A may include afirst reservoir 315, which houses a first film forming matrix. The firstfilm forming matrix generally includes film-forming components asdescribed above, and may include an active or it may be active-free. Theapparatus 310 includes a substrate 320, which is made from anon-ingestible material, such as mylar, paper, and other materialsdescribed above. The substrate 320, as with other embodiments describedabove, moves through the apparatus 310 in the direction represented bythe arrow A, i.e., from the first film forming region 310A to the secondfilm forming region 310B. The first film forming region 310A includes afirst manifold 325, which is in fluid connection with the firstreservoir 315, and is intended to deposit a continuous sheet 330 offirst film forming material onto the substrate 320 during use.Optionally, there may be a first drying apparatus (not shown) disposedat a location after the first manifold 325 but before the secondfilm-forming region 310B.

During use, the apparatus 310 deposits the sheet 330 of first filmforming material onto the substrate 320, forming a first layer of filmforming material. It may be desired that the sheet 330 of first filmforming material be immediately dried before entering the second filmforming region 310B. Alternatively, the sheet 330 of first film formingmaterial may be partially dried before entering the second film formingregion 310B, for example, to form a visco-elastic mass of film material.

The first layer of film forming material 330 (whether dried, undried, orpartially dried) travels through the apparatus 310 into the second filmforming region 310B. The second film forming region 310B may include thecomponents and methods described above with respect to the embodimentsdepicted in FIG. 1 or 2. For example, the second film forming region310B includes a second reservoir 340, which is in fluid communicationwith a second feed line 345. The second feed line 345 is incommunication with a plurality of volumetric pumps 350. The plurality ofvolumetric pumps 350 is in communication with a second manifold 355,which includes a plurality of orifices 360. As explained above,desirably, each orifice 360 is associated with one volumetric pump 350.The second film forming region 310 deposits a plurality of wet filmproducts 365 onto the first layer of film forming material 330 in asubstantially side-by-side manner in a series of columns (i.e., 370A,370B).

The first layer of film material 330 and the plurality of wet filmproducts 365 travel through the apparatus 310 into a drying apparatus375, which may be a drying oven. The wet film products 365 (and thefirst layer of film, if necessary) are dried, such as by the dryingmethods described above.

Once sufficiently dried, the resulting multi-layered film products(including the first layer 330 and the plurality of now-dried filmproducts 365) may be sized and cut as desired, or alternatively may bestored for future use. The first layer 330 and film products 365 aredesirably adhered to each other, which may be achieved simply throughthe drying process or there may be an adhesive composition appliedbetween the first layer 330 and the film products 365 prior todeposition thereof.

The present invention takes into account, and is premised on theunderstanding of, a number of issues that may adversely impact the flowof material through a slot die, which may result in changes in flow ofthe material. Slight changes in certain parameters may undesirably alterthe content uniformity of the resulting film, in particular theuniformity of active, which is produced across a plurality of slot diesfed from a single pump. Uniformity of content among individual films ordosages, particularly uniformity of active, is especially important infilm manufacturing. The present invention minimizes or all togethereliminates the potential problems associated with use of a single pump,as will be explained below.

In typical systems and in the present invention, a preferred slot die isa rectangular orifice having three dimensions: height (B), width (W) andlength (L). The length (L) is understood to be the length of the orificefrom the front of the die to the back, depicted in FIG. 1 as the lengthfrom the first side 65A and a second side 65B. The flow through arectangular die, such as the slot die of the present invention, may bedefined by the Hagen-Poiseuille equation:

$Q = {\frac{2}{3}\frac{\left( {P_{0} - P_{L}} \right)B^{3}W}{\mu \mspace{11mu} L}}$

In the above equation, Q is the volumetric flow rate, P is the pressure,and μ, is the viscosity of the fluid being flowed through the die. Whenmultiple orifices are being flowed through in typical apparatuses, suchas a slot die coater with a single pump feeding a manifold with multipleslot dies, the flow rate may be adversely impacted by many factors. Evenslight variations in these factors may have a significant impact in theflow rate, and thus the content of films formed by the apparatus. Thepotential adverse impact of such a system is reduced or eliminatedthrough the present invention.

For example, pressure changes may impact the flow rate, since flow isproportional to the pressure at the entrance to the slot in the slotdie. If a substantially uniform flow across multiple slot dies isdesired, it is important to have a substantially equal pressure level atthe entrance to each slot die. To achieve this equal pressure levelacross all dies, a manifold design with one single pump feeding to itmust prevent the flow inside the manifold from being disturbed byexternal forces. That is, the flow within such a manifold must not bedisturbed by changes in temperature, viscosity, or non-uniformdispersions or clumping of components in the fluid being flowed.

In addition, the height of the slot die may have an affect on the flowrate of the fluid being flowed through. Flow is proportional to theheight of the slot, which is typically the narrowest dimension of theslot die, to the third power. Since this is typically the smallestdimension, any variability in this dimension from slot to slot will havea potentially high impact on the percentage of variability in the flowrate of the matrix as it is fed to each of the slot dies. To counterthis problem, it would be critical that each of the slot dies in theapparatus have the same height dimension as each other. Even a 3%difference in height between adjacent slot dies in the apparatus wouldresult in a nearly 10% variation in flow rate.

Another factor that may affect the flow rate is the viscosity of thefluid being flowed through the dies. Flow rate is inversely proportionalto the viscosity, such that changes in the localized viscosity due toforces such as temperature or non-homogeneity (clumping of particles inthe matrix) will impact the flow rate through that slot, andsubsequently the flow rate through to the remaining slot dies. Even aslight change in the flow rate may adversely affect the uniformity ofcontent, including active content, of the films formed by subsequentslot dies.

In the present invention, the flow rate through each individual slot dieis determined and controlled by the flow exiting the individualvolumetric pump attached to an individual slot die. The presentinvention overcomes the above problems by using a plurality ofindividual pumps associated with individual slot dies. The pressure maybe kept at a substantially constant level among each individual pump. Inaddition, since each slot die is associated with an individual pump,variations in the height between adjacent slot dies will have no affecton each other. Finally, use of individual pumps may easily take intoaccount viscosity changes and minimize any potential affect based onvariations therein.

While the above problems may potentially be solved through the use of asingle pump-fed manifold directed to a plurality of individual slotdies, such an apparatus would need to include: a manifold that is notaffected by any external forces; identical slot dies; and a viscosity ofthe flowed matrix that is completely uniform with no drop in viscosityfrom the first slot die to the last slot die. Such an apparatus would becumbersome and difficult to achieve.

As can be appreciated by those of skill in the art, the presentinvention substantially solves the problems associated with suchsingle-pump apparatuses by providing a system and method that provideseach slot die with its own individual pump. The present system allowsfor greater control and stability between and among the slot dies in thesystem. The potential issues set forth in the Hagen-Poiseuille equationabove are rectified with the present invention in an efficient andcontrolled manner. The result is a more predictable and uniform productamong each slot die in the system.

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Further, the steps described above may be modified in various ways orperformed in a different order than described above, where appropriate.Accordingly, alternative embodiments are within the scope of thedisclosure.

1. A method of forming a plurality of individual film products,comprising the steps of: (a) providing a reservoir housing a filmforming matrix; (b) providing a plurality of individual volumetric pumpsin association with said reservoir; (c) providing a plurality oforifices, wherein each orifice is associated with an individualvolumetric pump; (d) feeding said film forming matrix from saidreservoir to said individual volumetric pumps; (e) dispensing apredetermined amount of said film forming matrix from each of saidvolumetric pumps through an orifice associated therewith; and (f)extruding a plurality of individual wet film products onto a substrate.2. The method of claim 1, wherein said substrate is a backing film. 3.The method of claim 1, wherein said substrate moves in a first directionfrom said plurality of orifices to a drying oven.
 4. (canceled)
 5. Themethod of claim 1, wherein steps (d)-(f) are repeated.
 6. The method ofclaim 5, wherein said individual wet film product is extruded onto aregion of said substrate onto which no individual wet film product hasalready been extruded. 7.-8. (canceled)
 9. The method of claim 1,wherein each of said individual volumetric pumps dispenses about 4microliters to about 250 microliters per stroke.
 10. The method of claim1, wherein said film forming matrix is at least 25% solids.
 11. Themethod of claim 1, further comprising the step: (g) Drying saidplurality of individual wet film products to form a plurality of driedindividual film products.
 12. The method of claim 11, wherein saidplurality of dried individual film products are die cut.
 13. The methodof claim 1, wherein said individual volumetric pumps are piston pumps.14.-16. (canceled)
 17. The method of claim 1, wherein each of saidorifices is a slot die.
 18. The method of claim 1, wherein each of saidindividual wet film products has substantially uniform content withrespect to each individual wet film product. 19.-29. (canceled)
 30. Anapparatus for forming a plurality of individual film products,comprising: (a) a reservoir for housing a film forming matrix; (b) aplurality of individual volumetric pumps associated with said reservoir;(c) a plurality of orifices, each orifice being associated with avolumetric pump; (d) a substrate; and (e) a means for moving saidsubstrate through said apparatus.
 31. The apparatus of claim 30, whereinsaid reservoir is pressurized.
 32. The apparatus of claim 30, whereinsaid individual volumetric pumps are rotating piston pumps.
 33. Theapparatus of claim 30, wherein each individual volumetric pumpdischarges about 4 microliters to about 250 microliters per stroke.34.-35. (canceled)
 36. The apparatus of claim 30, wherein the individualfilm products are small film products. 37.-38. (canceled)
 39. Theapparatus of claim 30, further comprising a drying oven.
 40. Theapparatus of claim 30, wherein said each of said orifices is a slot die.41. A method of forming a plurality of individual film patches,comprising the steps of: (a) providing a substrate comprising a sheet ofdissolvable polymeric material, said sheet having a top surface, whereinsaid substrate continuously moves in a first direction; (b) providing areservoir housing a wet film forming matrix, said wet film formingmatrix comprising a second polymeric material and an active; (c)providing a plurality of individual volumetric pumps in association withsaid reservoir; (d) providing a plurality of orifices, wherein eachorifice is associated with an individual volumetric pump, wherein eachorifice is separated from each other by a gap; (e) feeding said wet filmforming matrix from said reservoir to said individual volumetric pumps;(f) dispensing a predetermined amount of said film forming matrix fromeach of said volumetric pumps through an orifice associated therewith;(g) extruding said predetermined amount of said wet film forming matrixonto said top surface of said sheet to form a plurality of wet filmproducts; and (h) drying said wet film products to form a plurality ofmulti-layer film patches comprising a first layer comprising said sheetand a second layer comprising a dried film product. 42.-47. (canceled)